There are virtually no incontrovertible data elucidating the pathophysiology of the premature mortality, coronary artery disease, or osteoporosis seen in major depression. This is, of course, first and foremost an issue of patient survival and quality of life. Compelling data regarding pathophysiolgical mechanisms will also help formally establish major depression as a systemic disease in the general medical community. This, in turn, will elicit the surveillance of the medical community for systemic abnormalities in depressed patients, and the institution of effective preventive interventions to mitigate these systemic abnormalities. Contributing to this task could help highlight the urgency of diagnosing and treating depression, reduce the stigma of depression, and make it imperative for insurance companies to treat depression like any other systemic disease. We have identified an emerging metabolic syndrome in young, lean remitted patients with major depression, as well as premature osteoporosis, and are well on the way to ascertaining dysregulations among important mediators that could lead to the premature death and to both systemic manifestations. We found that compared to 47 BMI matched controls, remitted, young, lean patients with a major depressive illness had insulin resistance, increased plasma insulin, glucose, and triglyceride levels, as well as other serious sequella of insulin resistance and hyperinsulinism. Insulin exerts many adverse effects that are adaptive during acute stress but maladaptive when sustained. Insulin stimulates the secretion of proinflammatory cytokines such as IL-6, procoagulant compounds such as factor VIII, antifibrinolytic compounds such as PAI-1, and activates the sympathetic nervous system. We have found increased around-the-clock plasma IL-6 levels, and increased morning levels of factor VIII and PAI-1 levels, and unequivocal indices of sympathetic activation (the latter in patients with melancholic depression). It is of interest that both IL-6 and NE promote osteoporosis and coronary artery disease. One of our corollary goals is to identify common pathophysiolgical features that are involved in both premature osteoporosis and coronary artery disease. This work could also extend concepts of the metabolic syndrome as a syndrome that includes both the metabolic abnormalities cited above as well as pathologic bone loss. Our finding of continuous elevations of plasma IL-6 levels has several implications. IL-6 has pleotropic effects and itself causes insulin resistance, increased inflammation, increased clotting, and decreased fibrinolysis. IL-6 is implicated as a highly significant factor in both atherosclerosis, which has a strong inflammatory component, as well and osteoporosis. Plasma IL-6 levels in healthy individuals are the best predictor of subsequent coronary artery disease, exceeding C-reactive protein (CRP) in its predictive value. IL-6 levels also predict osteoporosis, and IL-6 is among the most potent inducer of bone resorption. In the post-menopausal period, one of the important mechanisms posited for this condition is the loss of estrogen-mediated suppression of IL-6 release. We also found that a group of unmediated depressed patients with melancholic depression had high, around-the-clock central and peripheral hypersecretion of NE, as well as of plasma epinephrine, and cortisol secretion. While depressed, they also had increased blood pressure and pulse rates; all were reversible by a centrally directed treatment, ECT. CSF NE, plasma NE, and plasma cortisol rose and fell together throughout the 24 hour period, and rose progressively during EEG-documented sleep, peaking in the early morning, the time of the highest incidence of sudden death and myocardial infarction. Plasma EPI levels were also very high at this point, as were plasma IL-6 levels in our former study. Central NE activatiion and peripheral hypersecretion of plasma NE, EPI, and cortisol are all cardiotoxic, and their rising and falling together throughout the 24 hour period could have a particularly adverse effects. In addition, patients with chronic heart failure complicated by depression have a doubling of morbidity and mortality. NE levels no higher than in our depressed patients were the best predictor of subsequent mortality and morbidity in chronic heart failure. This finding provides a mechanism for the deleterious effect of depression when superimposed upon another systemic disease. We first found that premenopausal women with major depression have a marked increase in the prevalence of osteopenia and osteoporosis. Compared to 3-4% of the general premenopausal population, we found a 20-25% of osteopenia or osteoporosis in our depressed patients. Extrapolating from our data, we estimate that over 400,000 premenopausal women with major depression have osteopenia or osteoporosis as a consequence of their depression. Unfortunately osteoporosis is a silent disease until a fracture occurs. It is, however, a highly treatable illness, highlighting the need for early detection. The incidence of osteopenia and osteoporosis in premenopausal women is alarmingly high, and a significant public health hazard. In summary, depression increases premature mortality, coronary artery disease, and osteoporosis. Our group conducting a program of clinical and translational research to ascertain the pathophysiology of these phenomena.